Exposure to Lead in Drinking Water Causes Cognitive Impairment via an Alzheimer's Disease Gene-Dependent Mechanism in Adult Mice

饮用水中的铅暴露通过阿尔茨海默氏病基因依赖机制导致成年小鼠认知障碍

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作者:Katharina Kohler, Teresa Macheda, Misty M Hobbs, M Tyler Maisel, Antonela Rodriguez, Lindsey Farris, Caitlin R Wessel, Christopher Infantino, Dana M Niedowicz, Alex M Helman, Tina L Beckett, Jason M Unrine, M Paul Murphy

Background

Exposure to lead (Pb) is a major public health problem that could occur through contaminated soil, air, food, or water, either during the course of everyday life, or while working in hazardous occupations. Although Pb has long been known as a neurodevelopmental toxicant in children, a recent and growing body of epidemiological research indicates that cumulative, low-level Pb exposure likely drives age-related neurologic dysfunction in adults. Environmental Pb exposure in adulthood has been linked to risk of late-onset Alzheimer's disease (AD) and dementia.

Conclusions

These results raise the possibility that the increased risk of dementia associated with Pb exposure in adults may be tied to its subsequent interaction with either pre-existing or developing AD-related neuropathology.

Methods

We investigated Pb exposure using a line of genetically modified mice with AD-causing knock-in mutations in the amyloid precursor protein and presenilin 1 (APPΔNL/ΔNL x PS1P264L/P264L) that had been crossed with Leprdb/db mice to impart vulnerability to vascular pathology.

Objective

Although the biological mechanism underlying this link is unknown, it has been proposed that Pb exposure may increase the risk of AD via altering the expression of AD-related genes and, possibly, by activating the molecular pathways underlying AD-related pathology.

Results

Our data show that although Pb exposure in adult mice impairs cognitive function, this effect is not related to either an increase in amyloid pathology or to changes in the expression of common AD-related genes. Pb exposure also caused a significant increase in blood pressure, a well known effect of Pb. Interestingly, although the increase in blood pressure was unrelated to genotype, only mice that carried AD-related mutations developed cognitive dysfunction, in spite of showing no significant change in cerebrovascular pathology. Conclusions: These results raise the possibility that the increased risk of dementia associated with Pb exposure in adults may be tied to its subsequent interaction with either pre-existing or developing AD-related neuropathology.

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